2 DOSAGE AND ADMINISTRATION RAVICTI should be prescribed by a physician experienced in management of UCDs. For administration and preparation, see full prescribing information. (2.1, 2.6) Switching From Sodium Phenylbutyrate Tablets or Powder to RAVICTI: Patients should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid, see full prescribing information for conversion. (2.2) Initial Dosage in Phenylbutyrate-Naïve Patients (2.3): Recommended dosage range is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity not adequately controlled with dietary restriction, the recommended starting dose is 4.5 mL/m2/day. Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence. Dosage Adjustment and Monitoring: Follow plasma ammonia levels to determine the need for dosage titration. (2.4) Dosage Modifications in Patients with Hepatic Impairment: Start dosage at lower end of range. (2.5, 8.6) 2.1 Important Administration Instructions RAVICTI should be prescribed by a physician experienced in the management of UCDs. Instruct patients to take RAVICTI with food or formula and to administer directly into the mouth via oral syringe or dosing cup. For patients who cannot swallow, see the instructions on administration of RAVICTI by nasogastric tube or gastrostomy tube [see Dosage and Administration (2.6)]. For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dose may be less than anticipated. Closely monitor these patients using ammonia levels [see Dosage and Administration (2.6)]. The recommended dosages for patients switching from sodium phenylbutyrate to RAVICTI and patients naïve to phenylbutyric acid are different [see Dosage and Administration (2.2, 2.3)]. For both subpopulations: Patients 2 years of age and older: Give RAVICTI in 3 equally divided dosages, each rounded up to the nearest 0.5 mL Patients 2 months of age to less than 2 years: Give RAVICTI in 3 or more equally divided dosages, each rounded up to the nearest 0.1 mL. The maximum total daily dosage is 17.5 mL (19 g). RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements). 2.2 Switching From Sodium Phenylbutyrate to RAVICTI Patients switching from sodium phenylbutyrate to RAVICTI should receive the dosage of RAVICTI that contains the same amount of phenylbutyric acid. The conversion is as follows: Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate tablets (g) × 0.86 Total daily dosage of RAVICTI (mL) = total daily dosage of sodium phenylbutyrate powder (g) × 0.81 2.3 Initial Dosage in Phenylbutyrate-Naïve Patients The recommended dosage range, based upon body surface area, in patients naïve to phenylbutyrate (PBA) is 4.5 to 11.2 mL/m2/day (5 to 12.4 g/m2/day). For patients with some residual enzyme activity who are not adequately controlled with protein restriction, the recommended starting dosage is 4.5 mL/m2/day. In determining the starting dosage of RAVICTI in treatment-naïve patients, consider the patient's residual urea synthetic capacity, dietary protein requirements, and diet adherence. Dietary protein is approximately 16% nitrogen by weight. Given that approximately 47% of dietary nitrogen is excreted as waste and approximately 70% of an administered PBA dose will be converted to urinary phenylacetylglutamine (U-PAGN), an initial estimated RAVICTI dose for a 24-hour period is 0.6 mL RAVICTI per gram of dietary protein ingested per 24-hour period. The total daily dosage should not exceed 17.5 mL. 2.4 Dosage Adjustment and Monitoring During treatment with RAVICTI, patients should be followed clinically and with plasma ammonia levels to determine the need for dosage titration. Closely monitor ammonia levels after changing the dosage of RAVICTI. Normal Ammonia Levels If patients experience symptoms of vomiting, nausea, headache, somnolence or confusion in the absence of high ammonia levels or other intercurrent illnesses, reduce the RAVICTI dosage and monitor patients clinically. If available, obtain measurements of plasma phenylacetate (PAA) concentrations and the ratio of plasma PAA to PAGN to guide dosing. A high PAA to PAGN ratio may indicate the saturation of the conjugation reaction to form PAGN. The PAA to PAGN ratio has been observed to be generally less than 1 in patients with UCDs without significant PAA accumulation [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. Elevated Ammonia Levels When plasma ammonia is elevated, increase the RAVICTI dosage to reduce the fasting ammonia level to less than half the upper limit of normal (ULN) in patients 6 years and older. In infants and pediatric patients (generally below 6 years of age), where obtaining fasting ammonia is problematic due to frequent feedings, adjust the dosage to keep the first ammonia of the morning below the ULN. Urinary Phenylacetylglutamine: If available, U-PAGN measurements may be used to help guide RAVICTI dosage adjustment. Each gram of U-PAGN excreted over 24 hours covers waste nitrogen generated from 1.4 grams of dietary protein. If U-PAGN excretion is insufficient to cover daily dietary protein intake and the fasting ammonia is greater than half the ULN, the RAVICTI dosage should be adjusted upward. The amount of dosage adjustment should factor in the amount of dietary protein that has not been covered, as indicated by the 24-hour U-PAGN level and the estimated RAVICTI dose needed per gram of dietary protein ingested and the maximum total daily dosage (i.e., 17.5 mL). Consider a patient's use of concomitant medications, such as probenecid, when making dosage adjustment decisions based on U-PAGN. Probenecid may result in a decrease of the urinary excretion of PAGN [see Drug Interactions (7.2)]. Plasma Phenylacetate and Phenylacetylglutamine: If available, the ratio of PAA to PAGN in plasma may provide additional information to assist in dosage adjustment decisions. In patients with a high PAA to PAGN ratio, a further increase in RAVICTI dosage may not increase PAGN formation, even if plasma PAA concentrations are increased, due to saturation of the conjugation reaction [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.5 Dosage Modifications in Patients with Hepatic Impairment For patients with moderate to severe hepatic impairment, the recommended starting dosage is at the lower end of the recommended dosing range (4.5 mL/m2/day) and kept at the lowest dose necessary to control the patient's ammonia levels [see Use in Specific Populations (8.7)]. 2.6 Preparation for Nasogastric Tube or Gastrostomy Tube Administration It is recommended that all patients who can swallow take RAVICTI orally, even those with nasogastric and/or gastrostomy tubes. However, for patients who cannot swallow, a nasogastric tube or gastrostomy tube may be used to administer RAVICTI as follows: Utilize an oral syringe to withdraw the prescribed dosage of RAVICTI from the bottle. Place the tip of the syringe into the nasogastric/gastrostomy tube. Utilizing the plunger of the syringe, administer RAVICTI into the tube. Flush once with 10 mL of water or formula and allow the flush to drain. If needed, flush a second time with an additional 10 mL of water or formula to clear the tube. For patients who require a volume of less than 1 mL per dose via nasogastric or gastrostomy tube, the delivered dosage may be less than anticipated due to adherence of RAVICTI to the plastic tubing. Therefore, these patients should be closely monitored using ammonia levels following initiation of RAVICTI dosing or dosage adjustments.